In the expiring NIH program we have generated and partially characterized a series of mouse mutants carrying defined defects in DNA repair systems with special emphasis on aspects related to aging. These experiments provided strong indications that defective processing of endogenously generated DNA damage interfering with transcription is an important cause of accelerated aging. This has supported the idea that DNA injury caused by free radicals and oxidative metabolism act pro-aging by blocking transcription triggering permanent cell growth, or cell death, exhausting the renewal capacity of a specific organ and inducing aging. In the current renewal we would like to go a significant step further. In addition to further validate the existing and new mouse models for aging and the development of more sophisticated conditional mouse models we intend also to generate reporter mice that allow repeated in vivo assessment of the aging/senescence status of an organ/animal. Finally we would like to exploit the rapidly aging mouse mutants for screening (mixture of) compounds that accelerate or preferentially delay the process of aging. This knowledge is not only relevant for insight into the molecular mechanism that underlies aging but at the same time it is a prerequisite for the development of rational design based anti-aging medication and advice on life style and environmental factors such as food.